P850: THE HUMORAL AND CELLULAR RESPONSE TO SARS-COV-2 MRNA VACCINATION IN PATIENTS WITH MULTIPLE MYELOMA AND PRE-MALIGNANT MONOCLONAL GAMMOPATHIES: IMPACT OF OMICRON VARIANT
Authors: P. Storti, V. Marchica, R. Vescovini, V. Franceschi, L. Russo, V. Raimondi, D. Toscani, J. Burroughs Garcia, N. T. Iannozzi, B. Dalla Palma, M. T. Giaimo, L. Notarfranchi, G. Donofrio, N. Giuliani
Journal: HemaSphere (2022)

Background: Multiple myeloma (MM) patients have a high risk of infections with a possible reduced response to vaccines including anti-SARS-CoV-2 one. Currently, the impact the emerging new variants in MM patients underwent to anti-SARS-CoV-2 vaccination is still unknown. Aims: The humoral and cellular response to SARS-CoV-2 mRNA full vaccination and booster dose and the impact of new spike-mutated variants, including Omicron have been investigated in a cohort of MM patients and those with pre-malignant monoclonal gammopathies. Methods: We enrolled 38 COVID-19-naïve patients: 6 monoclonal gammopathies of undetermined significance (MGUS), 10 smoldering myeloma (SMM), 9 newly diagnosed MM (NDMM) and 13 relapsed MM (MMR). Peripheral blood (PB) samples were collected before the first dose and 14±2 days after the second dose (POST) of the mRNA BNT162b2 vaccine. In a subset of 16 patients with MM (MMD and MMR), PB samples were also collected after 14±2 days of a heterologous booster dose (BOOSTER) with mRNA-1273 vaccine. SARS-CoV-2 spike IgG antibodies (Abs) were measured by the COVID-SeroIndex Kantaro SARS-CoV-2 IgG test. The fraction of neutralizing Abs (NAbs) against SARS-CoV-2 spike of Wuhan-Hu-1 strain and five variants (alpha, beta, gamma, delta and Omicron) was assessed in the collected sera by a SARS-CoV-2 pseudovirus neutralization assay. Finally, the collected PB-mononuclear cells were stimulated, with overlapping peptides pools spanning SARS-CoV-2 spike glycoprotein and SARS-CoV-2 spike-specific CD4+ and CD8+ T cells were identified by intracellular cytokine staining for Interferon-gamma (IFN-γ), interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-α), and CD107a+ using flow cytometry assay. Results: The seropositivity rate for SARS-CoV-2 spike IgG Abs in the total cohort was 86.8% with 13.2% patients exhibiting no detectable Abs. We found that MMR patients had significantly lower SARS-CoV-2 spike IgG Abs and NAbs compared with MGUS, SMM and NDMM patients after full vaccination. All the analyzed variants, remarkably Omicron, had a significant negative impact on the neutralizing ability of the vaccine-induced Abs in all patients with MM and also with SMM. We also observed a variable spike-specific CD4+ and CD8+ T cell responses. We found that both SMM and NDMM patients had significantly reduced spike-specific IL-2+CD4+ T cell responses compared to MGUS patients. MM patients showed reduced IFN-γ+ and TNF-α+CD8+ T cells, compared to MGUS. In BOOSTER samples, MMR patients retained significantly lower anti-spike-IgG-Abs levels compared to MMD patients. After the booster dose, MMD patients lost the negative impact of the spike variants seen after full vaccination, due to a significant increase of the NAbs titers. On the other hand, MMR patients retained NAbs titers against Beta, Delta and Omicron variants significantly lower than against Whuan-Hu-1 spike. The booster dose increased SARS-CoV-2 spike-specific T cells in both MMD and MMR reaching the 100% of responder patients with an increased percentage of IL-2+CD4+ T cells compared to full vaccination. Summary/Conclusion: Our study underlines the negative impact of Omicron variants on the neutralizing ability of the vaccine-induced Abs in MM patients as well as in SMM after a full vaccination. Booster dose immunization improved spike humoral and cellular responses in MMD patients and in most, but not all, MMR patients suggesting these patients need to be considered still at risk of Omicron SARS-CoV-2 infection with a clinically relevant disease.